Wednesday, June 7, 2023
6/7/2023
Abstract. The goal of cancer immunotherapy is to harness the immune system to destroy tumors in cancer patients. Two approaches have been successful in the clinic. (i) “Checkpoint blockade” therapies utilize blocking antibodies to inhibitory cell surface receptors or their ligands (CTLA4, PD-1/PD-L1) to deplete intratumoral regulatory T cells (Tregs) or to overcome a hyporesponsive state, termed “exhaustion” or “dysfunction”, that develops in CD8+ T cells that infiltrate solid tumors. However, only a subset of patients achieve complete remission, a problem that can potentially be countered by using combinations of antibodies to multiple inhibitory receptors. (ii) T cells expressing chimeric antigen receptors (CARs) that recognize tumor antigens are remarkably effective against hematopoietic cancers such as B-CLL (B cell chronic lymphocytic leukemia), but are not as effective against solid tumors, apparently because they become “exhausted” much like normal CD8 T cells responsive to standard peptide/MHC ligands. Here we propose a new strategy for increasing the effectiveness of CAR T cells attacking solid tumors. Some years ago, we discovered that TET (Ten-Eleven Translocation) enzymes are dioxygenases that use molecular oxygen, a-ketoglutarate (aKG) and reduced iron (Fe2+) to oxidize the methyl group of 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC) and additional oxidized methylcytosines that are all intermediates in DNA demethylation. We have shown in mouse models that TET deficiency results in skewed cell lineage specification and enhanced signal-dependent cell proliferation in many cell types; impairs the function of T regulatory (Treg) cells by decreasing the stability of Foxp3 expression; and improves the ability of splenic CD4+ and CD8+ tumor-infiltrating T cells (TILs) to promote tumor regression. Moreover, Tet2-deficient mouse CD8+ T cells displayed cell-intrinsic expansion and skewing towards a central memory phenotype, both homeostatically and in response to viral infection; Tet2 deficiency in myeloid cells resulted in decreased immunosuppression by tumor-associated macrophages and myeloid-derived suppressive cells, resulting in more effective tumor regression by tumor-infiltrating T cells; and TET2-deficient CAR T cells promoted complete remission when administered to a patient with chronic lymphocytic leukemia. Here we will test the hypothesis that TET loss-of-function in tumor-infiltrating CD8+ T cells (CD8 TILs) improves tumor rejection. In Aim 1, we will examine the role of TET proteins in the expansion and function of CD8+ TILs. The metabolite L-2-hydroxyglutarate (L-2HG) is a potent inhibitor of TET enzymes and other aKG- and Fe2+- dependent dioxygenases. L-2HG levels are normally maintained at very low levels in cells by the enzyme L- 2HG dehydrogenase (L2HGDH). In Aim 2, we will assess the effects of L2HGDH depletion or L-2HG pretreat- ment on CAR TILs. In Aim 3, we will delineate the transcriptional networks involving TET enzymes in CD8+ TILs.
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